Method for protecting and unprotecting the fluid path in a controlled environment enclosure

ABSTRACT

A controlled environment enclosure comprises a robotic arm manipulation system used to protect and unprotect a fluid path and a swab within the controlled environment enclosure. The apparatus allows the fluid path to be protected against dangerous decontamination vapors and chemicals before the controlled environment enclosure is decontaminated. The apparatus allows the fluid path to be unprotected without the use of gloves or other means that degrade the integrity of the controlled environment enclosure when decontamination is completed. The apparatus and method allow for the protecting, unprotecting and decontaminating sequences to be automated. In some embodiments the fluid path comprises a fill needle that can removably and aseptically be sealed with a disposable monolithic injection moulded polymeric fill needle sheath. The apparatus and method further allow for the use of a swab disposed in a swab holder that is aseptically and removably sealable to a swab cap to protect the swab against decontamination vapors.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a Divisional Application of U.S. patentapplication Ser. No. 16/901,123, filed Jun. 15, 2020, now U.S. Pat. No.______; which is a Divisional Application of U.S. patent applicationSer. No. 15/898,650, filed Feb. 18, 2018, now U.S. Pat. No. 10,684,303,which is a Divisional Application of U.S. patent application Ser. No.15/375,019, filed Dec. 9, 2016, now U.S. Pat. No. 10,067,151, whichclaims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application62/265,938 filed Dec. 10, 2015; and which claims priority to U.S. patentApplication Ser. No. 14/890,223, filed Jul. 27, 2016, which is a U.S.National Phase Entry of PCT Application PCT/US2012/047765, filed Jul.20, 2012, which claims priority under 35 U.S.C. § 119(e) to provisionalapplication 61/510,780 filed Jul. 22, 2011. All of these applicationsare herein incorporated by reference.

TECHNICAL FIELD

This document relates generally to apparatus and methods for use inhandling materials in controlled environment enclosures, includingapparatus and methods for aseptically filling pharmaceutical containersusing a fluid path that is protected and unprotected.

BACKGROUND

Controlled environment enclosures are known in the art. Such enclosuresare used, for example, for containment of hazardous materials. In otherexamples controlled environment enclosures are used to providecontrolled environments with limited numbers of particulates.

In the art controlled environment enclosures are typically fitted withports for transfer of materials in and out of the enclosure and theports are fitted with gloves for manual manipulation of equipment, partsor materials inside the enclosure. Such gloves are subject tosignificant risk of puncture.

In some examples known in the art the controlled environment enclosureis also used to limit exposure to viable particulates. Such controlledenvironment enclosures may be required for aseptic processing of cellcultures and for the manufacture of pharmaceutical products, medicaldevices, food or food ingredients. In these cases it is a requirementthat the controlled environment enclosure be decontaminated. This may bedone thermally using steam or chemically using chemical agents. Suitablechemical agents known in the art include hydrogen peroxide, ozone,beta-propiolactone, aziridine, formaldehyde, chlorine dioxide, ethyleneoxide, propylene oxide, and peracetic acid. In most cases thedecontamination and sterilization operations have to be preceded by acleaning process. Such cleaning processes have the function of removingmajor contamination by simple mechanical and chemical action.

In some examples in the prior art the controlled environment alsocontains automated equipment. Such automated equipment includes machinesfor filling of vials. The automated equipment located in the controlledenvironment is typically of such a size and complexity that it cannot beoperated fully automatically without human intervention. Such humanintervention typically requires the use of gloves with the associatedrisk of puncture.

Fluid paths within the controlled environment enclosures may be madefrom flexible tubing materials and can therefore have significant gaspermeability. Gases that naturally occur in air, such as oxygen andcarbon dioxide, as well as chemical decontamination agents, are known todiffuse into these tubing materials. Accumulation of these agents inflexible tubing and subsequent delayed release can be a majorcontamination problem during operation. This applies in particular toproducts or solutions that are sensitive to exposure to alkylatingagents, oxidizers, radicals or carbon dioxide. A typical example ofhuman intervention involving the use of gloves is the installation ofthe fluid path or multiple fluid paths after the completion ofdecontamination.

In view of the above there remains a need for controlled environmentsthat do not require human intervention via the use of gloves.

SUMMARY OF THE INVENTION

In one aspect of the invention there is provided a method for installinga fluid path within a controlled environment enclosure comprising,protecting the fluid path against an environment external to the fluidpath; introducing the fluid path into the controlled environmentenclosure; decontaminating the controlled environment enclosure; andmechanically unprotecting the fluid path within the controlledenvironment enclosure. The mechanically unprotecting can be by a roboticarm manipulation system. The decontaminating the controlled environmentenclosure is automatically done after the introducing the fluid pathinto the controlled environment enclosure. The unprotecting isautomatically done after the decontaminating the controlled environmentenclosure.

In one aspect of the invention there is provided a method fortransferring within a controlled environment enclosure a fluid along afluid path to a destination within the controlled environment enclosure,comprising protecting the fluid path against an environment external tothe fluid path; introducing the fluid path into the controlledenvironment enclosure; decontaminating the controlled environmentenclosure; mechanically unprotecting the fluid path within thecontrolled environment enclosure; and transferring the fluid to thedestination along the fluid path. The mechanically unprotecting can beby a robotic arm manipulation system. The fluid path can comprise apre-sterilized tube. The method can further comprise filtering the fluidin the fluid path and the filtering can be sterile filtering. Thedestination can be at least one of a culture of cells, a culture oftissue, an enzyme solution, a suspension of immobilized enzymes, a mixof active ingredients, and an excipient. The fluid can be an asepticfluid. The controlled environment enclosure can be an isolator. Thedestination can be microwell plates or containers for pharmaceuticalproducts.

In one aspect of the invention there is provided a method foruninstalling a fluid path from a controlled environment enclosure,comprising mechanically protecting the fluid path within the controlledenvironment enclosure; decontaminating the controlled environmentenclosure; opening the controlled environment enclosure; and removingthe fluid path from the controlled environment enclosure. Themechanically protecting can be by a robotic arm manipulation system. Thedecontaminating the controlled environment enclosure can be doneautomatically after the protecting the fluid path. The opening thecontrolled environment enclosure can be done automatically after thedecontaminating the controlled environment enclosure.

In one aspect of the invention there is provided a method fordecontaminating a controlled environment enclosure having a fluid path,the method comprising mechanically protecting by a robotic action thefluid path within the controlled environment enclosure; decontaminatingthe controlled environment enclosure; and opening and closing thecontrolled environment enclosure. The opening and closing the controlledenvironment enclosure can be done before or after the decontaminatingthe controlled environment enclosure. The mechanically protecting can beby a robotic arm manipulation system. The decontaminating the controlledenvironment enclosure can be done automatically after the mechanicallyprotecting the fluid path.

In one aspect of the invention there is provided an apparatus forprotection and unprotection of a fluid path within a controlledenvironment enclosure that includes a fluid path terminated by a fillneedle with removable sheath, and a remotely operated manipulationsystem for protection and/or unprotection of the fluid path. Theremotely operated manipulation system can include a robotic armmanipulation system. The apparatus can further include a tamper-evidentdevice positioned to reveal a breach of seal between the sheath and thefill needle. The apparatus can further include a removal station thatincludes a surface operative to interact with part of the sheath. Theremotely operated manipulation system can include a robot end toolincluding at least one surface that is shaped to hold the fill needle.The fluid path can be a pre-sterilized unit.

In one aspect of the invention there is provided an apparatus forinstalling a fluid path within a controlled environment enclosure thatincludes means for conveying the fluid, and remotely operated means forprotecting and/or unprotecting the means for conveying the fluid.

The inventors envision that compact and well-designed automatedequipment can be operated inside closed controlled environments withoutthe use of any gloves, eliminating thereby the risk of leaky gloves. Theinvention provides a method of installing a fluid path inside acontrolled environment enclosure without the use of gloves. Thisrequires the fluid path to be protected during the decontaminationprocess and to be unprotected prior to the use of the fluid path.Furthermore the fluid path can be automatically closed after use.

The closed fluid path can be re-opened and re-used at a later time. Thiscan be useful for continuing the use of the fluid path after unplannedevents that require breaking of the integrity of the enclosed controlledenvironment. Additionally the closing of the fluid path can beparticularly useful in situations where the fluid path has been in usefor transfer of hazardous substances. After closing of the fluid path,the enclosed environment can be cleaned and decontaminated; after whichthe fluid path can be removed.

In a first aspect of the invention a fluid handling assembly is providedfor automatically carrying out a fluid handling process in an asepticenvironment, the assembly comprising a first sheath portion including animplement portion disposed within the first sheath portion for use inthe process, a first locking mechanism portion, and a first sealingportion; a second sheath portion including a second locking mechanismportion configured to mate with positive detent with the first lockingmechanism portion, and a second sealing portion disposed to asepticallyseal with the first sealing portion when the first and second lockingmechanism portions are mutually mated, wherein the first and secondsheath portions define a sealed cavity that aseptically encapsulates theimplement portion when the first and second locking mechanism portionsare mutually mated. The assembly may be a fill assembly and theimplement portion comprises a proximal dispensing portion of a fillneedle, the fill needle including a fluid conduit that extends throughthe first sheath portion to a distal fluid supply end so that, when thefirst and second locking mechanism portions are mutually mated, theproximal dispensing portion of the fill needle is located inside thecavity and the distal fluid supply end of the fluid conduit is locatedoutside the cavity. The fluid conduit may include a flexible tube influid communication with the proximal dispensing portion of the fillneedle. The assembly may be a swab assembly with the implement portioncomprising a swab disposed inside the cavity when the first and secondlocking mechanism portions are mutually mated.

The assembly may further comprise a controlled environment enclosureconfigured to aseptically isolate the process and hold the fluidhandling assembly, and an articulated robot arm disposed within theenclosure to manipulate the fluid handling assembly. The first andsecond sheath portions may respectively comprise first and secondengagement portions. The assembly may further comprise a robotic armendpiece for the robotic arm, the endpiece configured to bear the firstsheath portion by engagement with positive detent with the firstengagement portion and a holding station comprising a first holdingfixture to hold the second sheath portion, the fixture configured forengaging with the second engagement portion. The holding station maycomprise angled fingers disposed to engage with the second engagementportion of the second sheath portion to release the first sheath portionfrom the second sheath portion. The holding station may comprise asecond holding fixture configured to suspend the mutually engaged firstand second sheath portions.

The first and second sheath portions may be separate injection moldedparts and wherein the locking mechanism portions include at least oneintegrally molded spring member. The assembly may further include atamper indicator that is mechanically linked to one of the lockingmechanism portions and includes a portion that is constructed toirreversibly tear in response to the mechanical separation of the firstand second sealing surfaces.

The first and second locking mechanism portions may be configured tomutually mate when the first and second locking mechanism portions aremoved towards each other along a locking axis. The first sheath portionmay further include a first bearing surface positioned at leastgenerally normal to the locking axis, and the second sheath portion mayfurther include a second bearing surface positioned at least generallynormal to the locking axis and facing the first bearing surface.

In a further aspect a method is provided for automatically carrying outa fluid handling process in controlled environment enclosure, the methodcomprising providing a first implement inside a first sealed sheath, thefirst sheath sealed by a detent-based sealing mechanism on the firstsheath that keeps the first sheath aseptically sealed around the firstimplement; placing the first sheath in the controlled environmentenclosure; decontaminating the controlled environment enclosure aroundthe first sheath after the step of placing; actuating the sealingmechanism to open the first sheath, and carrying out at least one stepin the fluid handing process with the implement in the controlledenvironment enclosure. The step of providing may include providing afill needle and wherein the step of carrying out includes carrying out afill operation. The step of decontaminating amay take place before thestep of carrying out a fill operation, further including a step of againactuating the sealing mechanism to seal the first sheath.

The method may further include an additional step of decontaminating thecontrolled environment chamber after the steps of carrying out a filloperation and again actuating the sealing mechanism. The method may yetfurther include providing a swab inside a second sealed sheath,providing a second detent-based sealing mechanism on the second sheaththat keeps the second sheath sealed around the swab, placing the secondsheath in the controlled environment enclosure, wherein the step ofdecontaminating decontaminates the outside of the second sheath, andswabbing the fill needle after the step of carrying out a filloperation.

The method may further include the steps of removing the first implementand the first sheath from the controlled environment enclosure,discarding the first implement and the first sheath, providing a secondimplement inside a second sealed sheath providing a second detent-basedsealing mechanism on the second sheath that keeps the second sheathsealed around the second implement, placing the second sheath in thecontrolled environment enclosure, decontaminating the controlledenvironment enclosure around the second sheath, and carrying out atleast one step in another run of the fluid handing process with theimplement in the aseptic environment.

The steps of actuating the first sealing mechanism and carrying out thefilling operation may be performed at least in part by a robotic armdisposed within the controlled environment enclosure. The method mayfurther include the step of providing a pre-sterilized tube asepticallysealed to the fill needle. The step of carrying out a fill operation mayinclude transferring fluid to at least one of a culture of cells, aculture of tissue, an enzyme solution, a suspension of immobilizedenzymes, a mix of active ingredients, and an excipient. The step ofcarrying out a fill operation may include transferring fluid to at leastone of microwell plates and containers for pharmaceutical products.

In a further aspect, a method is provided for automatically carrying outa fluid handling process in controlled environment enclosure,comprising: providing a plurality of disposable implements eachaseptically sealed inside one of a plurality of disposable sheaths,placing a first of the plurality of sealed sheaths that contains a firstof the plurality of implements in the controlled environment enclosure,decontaminating the controlled environment enclosure around the firstsheath after the step of placing the first sheath, opening the firstsheath, carrying out at least one step in the fluid handing process withthe first implement in the controlled environment enclosure, removingthe first sheath and the first implement from the controlled environmentenclosure, discarding the first implement and the first sheath, placinga second of the plurality of sealed sheaths that contains a second ofthe plurality of implements in the controlled environment enclosure,decontaminating the controlled environment enclosure around the secondsheath after the step of placing the second sheath, opening the secondsheath, carrying out at least one step in another run of the fluidhanding process with the second implement in the controlled environment,and repeating the steps of placing, decontaminating, opening, removing,and discarding for successive further ones of the plurality ofdisposable implements and corresponding ones of the plurality ofdisposable sheaths. The step of providing may provide a plurality ofdisposable implements that each include an intact tamper indicator. Thesteps of placing the first, second, and further sheaths may each includeplacing the intact tamper indicator for the sheath being placed, and thesteps of opening the first, second, and further sheaths may each includedisrupting the tamper indicator for the sheath being opened.

In a further aspect, a fluid handling assembly is provided forautomatically carrying out a fluid handling process in an asepticenvironment, comprising: a first sheath portion including an implementportion disposed within the first sheath portion for use in the process,a first locking mechanism portion, a first sealing portion, and a firstbearing surface positioned at least generally normal to a locking axis;a second sheath portion including: a second locking mechanism portionconfigured to mate with the first locking mechanism portion when thefirst and second locking mechanism portions are moved towards each otheralong the locking axis, a second sealing portion disposed to asepticallyseal with the first sealing portion when the first and second lockingmechanism portions are mutually mated, and a second bearing surfacepositioned at least generally normal to the locking axis and facingtoward the first bearing surface, wherein the first and second sheathportions define a sealed cavity that aseptically encapsulates theimplement portion when the first and second locking mechanism portionsare mutually mated.

In a further aspect, a fluid handling assembly is provided forautomatically carrying out a fluid handling process in an asepticenvironment, comprising: a first sheath portion including a swabdisposed within the first sheath portion for use in the process, and afirst sealing portion; and a second sheath portion including a secondsealing portion disposed to aseptically seal with the first sealingportion, wherein the first and second sheath portions define a sealedcavity that aseptically encapsulates the swab when the first and secondsealing portions are mutually mated.

In a further aspect, a method is provided for automatically carrying outa fluid handling process in controlled environment enclosure,comprising: providing a swab inside a first aseptically sealed sheath,placing the first sheath in the controlled environment enclosure,decontaminating the controlled environment enclosure around the firstsheath after the step of placing, opening the first sheath, and swabbingan implement used in the fluid handing process with the swab in thecontrolled environment enclosure.

Other features, elements, steps, characteristics and advantages of thepresent invention will become more apparent from the following detaileddescription of preferred embodiments of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not necessarily drawn to scale, like numeralsmay describe similar components in different views. Like numerals havingdifferent letter suffixes may represent different instances of similarcomponents. The drawings illustrate generally, by way of example, butnot by way of limitation, various embodiments discussed in the presentdocument.

FIG. 1 shows an apparatus for the protecting and unprotecting of a fluidpath in a controlled environment enclosure.

FIG. 2 shows detail of an end piece of an apparatus for the protectingand unprotecting of a fluid path in a controlled environment enclosure

FIG. 3 shows detail of a robotic arm forming part of an apparatus forthe protecting and unprotecting of a fluid path in a controlledenvironment enclosure

FIG. 4 is a flow chart for the typical prior art method.

FIG. 5 shows a method flow chart of an aspect of the invention.

FIG. 6 shows a method flow chart of another aspect of the invention.

FIG. 7 shows a method flow chart of another aspect of the invention.

FIG. 8 shows a method flow chart of another aspect of the invention.

FIG. 9a and FIG. 9b show isometric and sectional views respectively of acombination of a fill needle and a fill needle sheath, while FIG. 9cshows the combination of a fill needle and a fill needle sheath with atamper-indicator.

FIG. 10 shows a swab, swab sheath, and swab sheath cap for use with thesheath removal station of FIG. 12 and robotic arm end piece of FIG. 11.

FIG. 11 shows a robotic arm end piece according to one embodiment of theinvention for use with for use with the sheath removal station of FIG.12 and the fill needle and fill needle sheath of FIG. 9a and FIG. 9 b.

FIG. 12 shows a sheath removal station according to one embodiment ofthe invention.

FIG. 13 shows the sheath removal station of FIG. 2 with a swab packageand fill needle package suspended on the sheath removal station beforeuse.

FIG. 14a shows the fill needle package of FIG. 9a and FIG. 9b held bythe robotic arm end piece of FIG. 11.

FIG. 14b shows the fill needle package of FIG. 9a and FIG. 9b as well asthe swab package of FIG. 10 held by the robotic arm end piece of FIG.11.

FIG. 15 shows a flow chart of (a) method for transferring within acontrolled environment enclosure a fluid along a fluid path to adestination within the controlled environment enclosure and (b) a methodfor installing a fluid path in the controlled environment enclosure.

FIG. 16 shows a flowchart of a method for uninstalling from a controlledenvironment enclosure a fluid path comprising a fill needle.

DETAILED DESCRIPTION

FIG. 1 shows an embodiment of an apparatus for protecting andunprotecting of a fluid path 404 in a controlled environment enclosure420. The term “fluid” as used herein denotes any liquid, gas, liquid-gasmixtures and any mixture of solids in liquid that has fluid attributes,such as flowability or having appreciable fluidity at ambienttemperature and pressure, including, without limitation, a dispersion ofa solid or solids in a liquid, an emulsion, a slurry, a micro-emulsion,colloidal suspension, a suspension, a suspension of liposomes, and asuspension of micelles or the like. The term “fluid path” as used hereindenotes any single channel or multi channel tubing, rigid or flexible,for transporting a fluid.

A fluid path 404 starts at a container 401. The term “container” as usedherein denotes any vessel suitable to hold a fluid, including withoutlimitation any vial, syringe, ampoule, carpule, bottle, flask, beaker,bag, well in multi-well plates, or tube. The container 401 is fittedwith an air filter 402. The container 401 can be equipped with optionalsensors (not shown) to measure volume, weight of fluid, or otherparameters. In some embodiments there can be multiple containersconnected in parallel or in series with one another. Along the fluidpath 404 there can be optional measuring devices (not shown) thatmeasure properties, including without limitation any one or more ofpressure, flow, temperature, density and conductivity. The fluid path404 can be fitted with a filter element 403. The filter element 403 canbe selected to be suitable for sterile filtration of fluids.

In FIG. 1 the fluid path 404 comprises flexible tubing 405 and entersthe controlled environment enclosure 420 via a sealed opening (notshown). The sealing can be, for example, via the use of a suitableaseptically sealing flange (not shown), which may seal by means of, forexample without limitation, an aseptic tri-clamp. The container 401 andair filter 402 can be located outside the controlled environmentenclosure 420, as shown in FIG. 1. In other embodiments of the inventionthe container 401 and air filter 402 can be located inside thecontrolled environment enclosure 420.

Controlled environment enclosure 420 is equipped with an inlet filter430, an inlet valve 431, a blower 432, an outlet filter 433 and anoutlet valve 434. The characteristics of blower 432, inlet filter 430and outlet filter 433 are chosen to yield a controlled environmentinside controlled environment enclosure 420. As understood by thoseskilled in the art, various other filter and blower arrangements arepossible to establish a controlled environment inside controlledenvironment enclosure 420. A suitable controlled environment can beobtained, for example without limitation, by means of any one or more ofturbulent airflow, horizontal unidirectional airflow and verticalunidirectional airflow.

The fluid from container 401 can be transferred through the fluid path404 by a number of different mechanisms, including without limitation aperistaltic pump 410 as shown in FIG. 1, a difference in pressurebetween the container 401 and the controlled environment enclosure 420,a difference in static height of the container 401 and the end of thefluid path 404, a gear pump, a lobe pump, a membrane pump, a pistonpump, or a syringe pump. In FIG. 1, pump 410 is shown disposed insidecontrolled environment enclosure 420. In other embodiments, pump 410 maybe disposed outside controlled environment enclosure 420.

The flexible tubing 405 of the fluid path 404 can terminate with an endpiece 414. A suitable end piece can be, for example without limitation,a fill needle, a pipette dispensing system, a syringe dispensing system,a valve dispensing system, quick connectors, aseptic connectors,dispense tips and a needle for piercing of elastomers. In FIG. 1 the endpiece 414 is selected to be a fill needle.

The end piece 414 can be manipulated inside the controlled environmentenclosure 420 by mechanical means, for example, a robotic armmanipulation system 415. A suitable robotic arm manipulation system 415may be an articulated robotic arm. Suitable robotic arm manipulationsystems for mechanically manipulating end piece 414 include, but are notlimited to, 6-axis robotic arms, Selective Compliant Articulated RobotArm (SCARA) systems, r-theta robots, or combinations of linear actuatorsand rotary actuators.

Fluids are transferred along the fluid path 404 to a destination, whichcan be containers such as the tray with vials 411 located on pedestal412 in FIG. 1. The destination may be microwell plates forpharmaceutical products.

The fluid path 404 may be employed for a variety of purposes includingwithout limitation the filling of empty containers, washing and rinsingof containers, adding fluid to containers with a freeze dried powder,adding fluids to containers containing excipients and/or activeingredients, adding medium to cells, tissue or microbes, inoculatingcells or microbes, adding substrate to enzyme solutions or suspensionsof immobilized enzymes, adding gases such as argon or nitrogen to createan inert head space in containers, adding gases such as nitrogen, air orcarbon dioxide to cells and removing fluids out of containers bysuction. The term “excipient” as used herein denotes an inert substanceused as a diluent or vehicle for a drug.

Fluid path 404 may in some applications be required for aseptic transferof fluids. In such a case fluid path 404 can be pre-sterilized beforeinstallation in the controlled environment enclosure 420. The asepticpart of the fluid path 404 can start with container 401 or with filter403. Installation of the aseptic fluid path 404 requires sealing of theend piece 414.

FIG. 4 is a flowchart showing the prior art method for installing afluid path in a prior art controlled environment enclosure. The priorart method requires the steps in sequence of decontaminating (100) theprior art controlled environment enclosure; transferring (110) the fluidpath into the prior art controlled environment enclosure; and installing(120) by hand the fluid path in the prior art controlled environmentenclosure, before using (130) the fluid path for the purpose for whichit is intended.

In an aspect of the invention there is provided a method for installinga fluid path 404 in the controlled environment enclosure 420. Referringto the apparatus of FIG. 1 and the flow chart of FIG. 5, the methodcomprises protecting (301) the fluid path 404 against an environmentexternal to the fluid path 404, introducing (302) the fluid path 404into the controlled environment enclosure 420, decontaminating (303) thecontrolled environment enclosure 420, and mechanically unprotecting(304) the fluid path 404. In its unprotected state fluid path 404 canthen be used for transporting (305) fluids to destination 411, whichfluids can be aseptic or sterile fluids. Such transporting (305) offluids can comprise filtering the fluid in the fluid path 404 usingfilter element 403 and the filtering can be sterile filtering. The terms“sterile” and “aseptic” are used interchangeably in this specification.The term “decontamination” as used herein denotes a process for removingor inactivating contamination, including without limitation viruses,bacteria, spores, prions, molds, yeasts, proteins, pyrogens andendotoxins, to acceptable levels. “Decontamination” as used hereinincludes both sterilization (that is, the destruction of allmicroorganisms, including bacterial spores to a probability of survivingorganisms of typically less than 1:10⁶) and disinfection (that is, thedestruction and removal of specific types of micro-organisms).

In FIG. 2 a suitable arrangement for mechanically unprotecting (304)fluid path 404 is shown, comprising end piece 414 of fluid path 404 inthe form of a fill needle, together with a fill needle sheath 503. Thefill needle 414 comprises fill needle tubing 501 and fill needle hub502. Fill needle tubing 501 is in fluid communication with fluid path404 of FIG. 1 and is aseptically joined to fluid path 404. When thefluid path 404 is within controlled environment enclosure 420, the fillneedle sheath 503 can be stored in a sheath removal station 413 of thecontrolled environment enclosure 420 shown in FIG. 1.

The fill needle hub 502 and the fill needle tubing 501 can be glued orwelded together. In alternative embodiments the fill needle hub 502 andthe fill needle tubing 501 can be made as one part out of solidmaterial. The fill needle sheath 503 can be manufactured using materialswith different thermal expansion coefficients to allow it to slide onand off the fill needle hub 502 after thermal expansion. Alternativelythe fill needle sheath 503 can be designed to have a sliding fit on thefill needle hub 502 using porous PTFE or a steam permeable elastomericmaterial.

Protecting (301) the fluid path 404 comprises sealingly placing the fillneedle sheath 503 over the fill needle 414 such that the fill needlesheath 503 seals with the needle hub 502. The fill needle sheath 503 andneedle hub 502 can be equipped with one or multiple of tamper evidentfeatures 504 that will provide evidence of breaking the seal betweenneedle hub 502 and fill needle sheath 503. Possible tamper evidentfeatures 504 include but are not limited to heat shrink bands, tapeseals, breakable rings, tear-off connectors and snap connect tear-offconnectors. Unprotecting (304) the fluid path 404 comprises removing thefill needle sheath 503 from the fill needle 414, thereby exposing thefill needle 414 to an environment within the controlled environmentenclosure 420. When the fill needle 414 is in use within the controlledenvironment enclosure 420, the fill needle sheath 503 is stored in thesheath removal station 413.

The mechanically unprotecting (304) the fill needle 414 when it iswithin controlled environment enclosure 420 can comprise using a roboticarm manipulation system 415 shown in FIG. 1. FIG. 3 illustrates part ofthe robotic arm manipulation system 415 of FIG. 1, wherein a forearm 601is connected to a wrist 602, and the wrist 602 is connected to a toolflange 603. The end tool 604, shown in FIG. 3 as being fork shaped, hasa partially opened bore of such diameter that the end tool 604 can slidearound a narrow tubular section of needle hub 502 and the end tool 604can move upwards to establish a precise locating fit to needle hub 502.For unprotecting (304) the fill needle 414, the end tool 604 moves thefill needle 414 with the fill needle sheath 503 and places the fillneedle 414 with the fill needle sheath 503 in sheath removal station413.

In one embodiment of the apparatus and method, the sheath removalstation 413 heats the fill needle sheath 503, which thereby expands andreleases its grip or seal to the needle hub 502. Practitioners in thefield will appreciate that there are many different ways by which thefill needle sheath 503 can be removed from the fill needle 414. The endtool 604, through the motion of the robotic arm manipulation system 415,removes the fill needle 414 from the fill needle sheath 503. The fillneedle sheath 503 can remain in the sheath removal station 413 while therobotic arm manipulation system 415 moves the fill needle 414 to thedestination. In one embodiment of the apparatus and method thedestination shown is the tray with vials 411 located on the pedestal 412in FIG. 1.

The end tool 604 and the needle hub 502 can have various different othershapes allowing the use of various other closure systems such as, forexample without limitation, a plug, a cap with sliding fit o-ring sealwith minimal occluded surface area, a cap with membrane peel-off seal,or a twist-off cap. As understood by those skilled in the art, someclosure systems will be more suitable than other closure systems for usewith particular sterilization methods.

Materials of lesser permeability can be used in the manufacture of theflexible tubing 405, but this is not always an option. Tubingpermeability can also be reduced by adding additional layers to thetubing. Example methods for establishing such additional layers aroundthe flexible tubing 405 include, but are not limited to, heat shrinkingwith non-permeable polymers such as FEP, multilayer co-extrusion withnon-permeable polymers, creating a diffusion barrier by polymericcoating such as poly(p-xylylene), encasing with layers of tape, and thefitting of a sleeve.

In a further aspect of the invention there is provided a method foruninstalling a fluid path 404 from the controlled environment enclosure420. Referring to the apparatus of FIG. 1 and the flow chart of FIG. 6,the method comprises mechanically protecting (306) the fluid path 404within the controlled environment enclosure 420 once the use of fluidpath 404 has been completed, decontaminating (303) the controlledenvironment enclosure 420, and removing (307) the fluid path 404 fromthe controlled environment enclosure 420. The mechanically protecting(306) the fill needle 414 can comprise using the robotic armmanipulation system 415 shown in FIG. 1.

The mechanically protecting (306) the fill needle 414 within controlledenvironment enclosure 420 can comprise using the robotic armmanipulation system 415 of FIG. 1. The end tool 604 (See FIG. 3) ofrobotic arm manipulation system 415 is used to move the fill needle 414to and place it in the fill needle sheath 503, which is housed in thesheath removal station 413. The sheath removal station 413 heats thefill needle sheath 503 until the fill needle sheath 503 can slide overfill needle 414 to suitably seal to needle hub 502 after cooling, tothereby protect (306) the fill needle 414 within controlled environmentenclosure 420. The robotic arm manipulation system 415 can then furthermove the protected fluid path 404 as may be required.

In a further aspect of the invention the mechanically unprotecting (304)and the mechanically protecting (306) the fill needle 414 using therobotic arm manipulation system 415 can be done automatically. Forexample, a suitable controller 440 (see FIG. 1), communicating controlinstructions with the controlled environment enclosure 420 via a controlline 450, can be programmed to automatically unprotect (304) the fillneedle 414 using the robotic arm manipulation system 415 once thedecontaminating (303) the controlled environment enclosure 420 has beencompleted. Such automation obviates human intervention in the step ofmechanically unprotecting (304) the fill needle 414. In an embodiment ofthe method, the step of decontaminating (303) the controlled environmentenclosure 420 can also be managed by controller 440. This allows theremainder of the steps of installing the fill needle 414, beyond thestep of introducing (302) the fluid path 404 into the controlledenvironment enclosure 420, to be automated using controller 440,including the use of the fill needle for the purpose for which it isinstalled, and the mechanically protecting (306) the fill needle 414after such use.

In a further aspect of the invention there is provided a method fordecontaminating the controlled environment enclosure 420 having a fluidpath 404. The method comprises mechanically protecting (306) the fluidpath 404 within the controlled environment enclosure by sealinglyplacing the fill needle sheath 503 over the fill needle 414 such thatthe fill needle sheath 503 seals with the needle hub 502;decontaminating (303) the controlled environment enclosure 420; andopening (308) and closing (309) the controlled environment enclosure420. The opening (308) and closing (309) the controlled environmentenclosure 420 can be done after the decontaminating (303) the controlledenvironment enclosure 420, as may be the case when the fluid or thematerials at the destination 411 are dangerous. This is shown in FIG. 7.Alternatively, the opening (308) and closing (309) the controlledenvironment enclosure 420 can be done before the decontaminating (303)the controlled environment enclosure 420. This is shown in FIG. 8, asmay be the case when the external environment holds potential ofcontaminating the fluid or the materials at the destination 411. Themechanically protecting (306) the fill needle 414 can comprise using therobotic arm manipulation system 415 shown in FIG. 1, as alreadydescribed.

The protecting (306) the fill needle 414 using the robotic armmanipulation system 415 can be done automatically via controller 440(see FIG. 1). Controller 440 can be programmed for automaticallymechanically protecting (306) the fill needle 414 using the robotic armmanipulation system 415, prior to opening (308) and closing (309) thecontrolled environment enclosure 420. The opening (308) and closing(309) the controlled environment enclosure 420 can likewise be automatedvia controller 440.

We have described thus far herein an embodiment of a sheath removalstation 413 of FIG. 1 based on employing heat to secure or release fillneedle 414 from fill needle sheath 503. We now turn to anotherembodiment of the subsystem comprising sheath removal station 413′, fillneedle 414′, fill needle sheath 503′, and robotic arm manipulationsystem 415 described at the hand of FIGS. 9a, 9b , 10 and 11. In thisembodiment, we describe an alternative sheath removal system andassociated sheath removal station 413′, and provide more detail asregards fill needle 414′, fill needle sheath 503′, and robotic armmanipulation system 415.

FIG. 9a and FIG. 9b provide isometric and sectional views respectivelyof the fill needle sheath 503′ and fill needle 414′ combination 900 ofthis embodiment. The term “aseptically sealed fill needle package” 900will be used in the present specification to describe this combinationof mutually aseptically sealed fill needle sheath 503′ and fill needle414′. While FIG. 9a provides perspective, the simplicity of FIG. 9ballows more elements to be clearly indicated and numbered. Fill needlesheath 503′ comprises a substantially cylindrical vessel portion 910configured to receive the dispensing end of fill needle 414′, and twoclamping members 930 a and 930 b attached to vessel portion 910 byspring loaded members 920 a and 920 b respectively. In one embodiment,shown in FIG. 9a and FIG. 9b , the spring loading is established bymeans of the natural elastic flexibility of members 920 a and 920 b. Tothis end, fill needle sheath 503′ may be manufactured from a polymericmaterial with suitable inherent elasticity and that is compatible withaseptic systems requirements. Locating eyelets 950 a and 950 b aredisposed in clamping members 930 a and 930 b respectively. Clampingmembers 930 a and 930 b further comprise clamping clips 960 a and 960 brespectively disposed to engage with filling needle 414′ as described inmore detail below.

Filling needle 414′ may be configured in many different ways. In thepresent non-limiting exemplary embodiment, fill needle 414′ comprisesfill needle tubing 501′ and fill needle hub 502′. Fill needle 414′comprises a dispensing portion 506′, being the dispensing tip of fillneedle 414′. Fill needle tubing 501′ is in fluid communication withfluid path 404 of FIG. 1 and is aseptically joined to fluid path 404.Fill needle hub 502′ mates axially face-to-face with fill needle sheath503′ in an aseptic pressure seal provided by elastically compressibleO-ring 940. Fill needle hub 502′ further comprises locating ledges 508a′ and 508 b′ for engaging with clamping clips 960 a and 960 b offilling needle 414′. In manufacture, spring loaded members 920 a and 920b are fashioned to be spring loaded when clamping clips 960 a and 960 bare engaged with locating ledge 508′. When filling needle 414′ issheathed in fill needle sheath 503′ with compressible O-ring 940 undersuitable compression, clamping clips 960 a and 960 b are engaged withlocating ledge 508′ and under a tension force directing clips 960 a and960 b towards each other. Under these circumstances, the tension in fillneedle sheath 503′ is contained in spring loaded members 920 a and 920b. Other embodiments for urging clips 960 a and 960 b towards each otherwhen filling needle 414′ is sheathed in fill needle sheath 503′ arecontemplated, including embodiments in which discrete springs areemployed to render members 920 a and 920 b spring loaded.

Fill needle sheath 503′ may be manufactured by injection molding of asuitable polymeric material. In order to keep units costs low it mayspecifically be injection molded as a single monolithic unit. In thepresent specification the term “monolithic” is employed to describe anobject that is fashioned is a contiguous whole from one piece ofmaterial without joints or seams, whether by casting, molding, ordeposition, or any other means. A single mold in the art of injectionmolding generally produces a monolithic product. The locking memberportions of fill needle hub 502′ and the fill needle sheath 503′ may inparticular be integrally molded. This includes in particular springloaded members 920 a and 920 b.

Fill needle hub 502′ comprises two engagement clips 510 a′ and 510 b′for engaging with robotic arm end piece 1100 of FIG. 11. The operationof these will be described below at the hand of FIG. 11. Engagementclips 510 a′ and 510 b′ are able to flex such that their top ends can bedeflected closer together while engagement clips 510 a′ and 510 b′ canpush back in reaction against whatever bodies are pushing them together.To this end engagement clips 510 a′ and 510 b′ may be spring loaded. Inthe embodiment of fill needle hub 502′ shown in FIGS. 9a and 9b ,engagement clips 510 a′ and 510 b′ are flexible by virtue of beingmanufactured from an elastic material such as, for example withoutlimitation, a suitable polymeric material compatible with aseptichandling requirements. Engagement clips 510 a′ and 510 b′ are shaped toboth clip over robotic arm end piece 1100 of FIG. 11 and be deflectedtoward each other by end piece 1100.

In the embodiment shown in FIG. 9a and FIG. 9b , fill needle hub 502′ isshown as comprising several interior substructures. This approach allowsthe same mold to be employed for the manufacture by injection molding ofall fill needle hubs, while the interior substructures are then adaptedto differently sized fill needle tubing 501′. This allows costs to bekept low. Other arrangements of substructures are also contemplated,including without limitation embodiments wherein the entire fill needlehub 502′ is one monolithic entity fashioned by injection molding of asuitable polymeric material compatible with aseptic requirements. Basedon the above, fill needle package 900 comprises first and second sheathportions that together define a sealed cavity that asepticallyencapsulates an implement portion when first and second lockingmechanism portions are mutually mated.

In view of the above, flow path 404 of FIG. 1, as supplied for use inthis embodiment, comprises flexible tubing 405, an aseptically sealingflange for aseptically sealing the flow path 404 to the controlledenvironment chamber 420, and aseptically sealed fill needle package 900.

Turning now to FIG. 9 c, aseptically sealed fill needle package 900 mayhave a tamper indicator 970 that is mechanically linked to one of thelocking mechanism portions of fill needle package 900. In FIG. 9c tamperindicator 970 comprises a tearable strip across spring loaded members920 a and 920 b. When locating eyelets 950 a and 950 b are forced apart,the portion of tamper indicator 970 disposed across spring loadedmembers 920 a and 920 b is torn irreversibly. Since the same act ofseparating locating eyelets 950 a and 950 b also leads to the separationof sealing surfaces between the fill needle hub 502′ and the fill needlesheath 503′, the breaking of tamper indicator 970 is a direct indicatorof the breach of the aseptic seal between fill needle hub 502′ and fillneedle sheath 503′. The same tamper-evident arrangement may be made forthe swab system described below.

As part of the process of filling a pharmaceutical container with apharmaceutical product, a regulatory requirement may exist in some casesfor the dispensing tip of the fill needle 414,414′ to be swabbed with asuitable swab to collect potential contamination species. Such swabs arethen typically evaluated by a suitably qualified laboratory in order toassess the aseptic state of the pharmaceutical dispensing process. Tothis end, in another aspect of the invention, an asepticallysealable/unsealable swab subsystem is provided. In FIG. 10, swabsubsystem 1000 comprises a swab holder 1003 that may usefully be of thesame design as fill needle sheath 503′ of FIG. 9a and FIG. 9b . Swab1006 is mounted within swab holder 1003 with the collection tip 1008 ofswab 1006 protruding above the top of swab holder 1003. This arrangementallows the dispensing tip of the fill needle 414,414′ to be swabbed bytouching the dispensing tip to the collection tip 1008 of swab 1006.Swab holder 1003 may be a monolithic injection molded polymeric swabholder.

Swab subsystem 1000 further comprises a swab holder cap 1002 that mayusefully be of the same design as fill needle hub 502′ of FIG. 9a andFIG. 9b , with this modification that swab holder cap 1002 has no fillneedle tube 502′ and that swab holder cap 1002 is instead permanentlysealed at the top. As regards all other mechanical operational aspects,fill needle sheath 503′ and fill needle 414′ combination 900 and swabsubsystem 1000 may be identical. For this reason, the mechanical designaspects of swab subsystem 1000 will not be further discussed here. Weshall, however, be referring below to engagement clips 1010 a′ and 1010b′ of swab holder cap 1002 as regards their engagement with robotic armend piece 1100 of FIG. 11. We shall also be referring below to locatingeyelets 1050 a and 1050 b disposed in clamping members 1030 a and 1030 brespectively as regards their engagement with fingers. The term“aseptically sealed swab package” 1000 will be used in the presentspecification to describe this combination of mutually asepticallysealed swab holder cap 1002 and swab holder 1003 containing swab 1006.The swab 1006 is supplied for use packaged in the form of asepticallysealed swab package 1000. Based on the above, swab package 1000comprises first and second sheath portions that together define a sealedcavity that aseptically encapsulates an implement portion when first andsecond locking mechanism portions are mutually mated. The locking memberportions of f swab holder cap 1002 and the swab holder 1003 may inparticular be integrally molded. This includes in particular springloaded members of the structure.

FIG. 11 shows one embodiment of an endpiece 1100 for robotic arm 415 ofFIG. 1 configured to engage with swab subsystem 1000 of FIG. 10 and withfill needle sheath 503′ and fill needle 414′ combination 900 of FIG. 9aand FIG. 9b . Flange 1110 is disposed and shaped for attaching endpiece1100 to robotic arm 415 of FIG. 1. Openings 1120 and 1140 are disposedand shaped for holding fill needle 414′ and swab holder cap 1004respectively. In the case of fill needle 414′, engagement clips 510 a′and 510 b′ of fill needle hub 502′ engage with end piece engagementsurfaces 1120 a and 1120 b of endpiece 1100.

Procedurally, fill needle 414′ is engaged as follows with endpiece 1100.Endpiece 1100 is moved forward over the part of fill needle tubing 501′that protrudes out of fill needle 414′ and any associated section offlow path 404 joined to fill needle tubing 501′ until opening 1120 isdirectly above fill needle 414′. In this process, opening 1120 c allowsendpiece 1100 to negotiate fill needle tubing 501′. Endpiece 1100 maythen be lowered such that the bottom edges of engagement surfaces 1120 aand 1120 b engage with the sloped portions of engagement clips 510 a′and 510 b′. When endpiece 1100 is lowered further, engagement clips 510a′ and 510 b′ are both flexibly deflected towards each other untilengagement surfaces 1120 a and 1120 b pass the sloped portions ofengagement clips 510 a′ and 510 b′ and engagement clips 510 a′ and 510b′ snap back to engage their flat surfaces with engagement surfaces 1120a and 1120 b of endpiece 1100. This securely locates fill needle 414′ inendpiece 1100. When fill needle 414′ is engaged with endpiece 1100,clamping members 930 a and 930 b are disposed in slots 1130 a and 1130 brespectively so as to render locating eyelets 950 a and 950 baccessible.

In the case of swab holder cap 1004, the engagement proceeds in the samefashion, except that there is no fill needle tubing 501′ requiring anopening similar to 1120 c. Endpiece 1100 is simply moved until opening1140 is directly above swab holder cap 1004, after which endpiece 1100is lowered such that the flat surfaces of engagement clips 1010 a′ and1010 b′ engage with surfaces 1140 a and 1140 b of opening 1140 in afashion similar to that described above for engagement clips 510 a′ and510 b′. When swab holder cap 1004 is engaged with endpiece 1100,clamping members 1030 a and 1030 b are disposed in slots 1150 a and 1150b respectively so as to render locating eyelets 1050 a and 1050 baccessible.

When first using a fill needle 414, 414′ and flow path 404, the productto be dispensed into containers is first run through the flow path 404and fill needle 414, 414′ to establish a steady and reliable flow. Thisinitial volume of product may be dispensed into a priming bottle to bedisposed of later. Grip 1160 on endpiece 1100 may be employed as ageneral tool for handling, for example, stoppers for such primingbottles and the like.

To describe the removal of fill needle sheath 503′ from fill needle414′, we turn now to FIG. 12, in which sheath removal station 413′comprises sheath engagement fingers 1220 a and 1220 b for engaging withlocating eyelets 950 a and 950 b of fill needle sheath 503′. When fillneedle sheath 503′, either with or without fill needle 414′ engaged withit, is forced onto sheath engagement fingers 1220 a and 1220 b, theangled mutual orientation of sheath engagement fingers 1220 a and 1220 bforces apart clamping members 930 a and 930 b of fill needle sheath503′. This action forces clamping clips 960 a and 960 b apart anddisengages clamping clips 960 a and 960 b from locating ledge 508′ offill needle hub 502′. O-ring 940 thereby is allowed to expand to itsuncompressed state and fill needle 414′ is released from fill needlesheath 503′. Fill needle sheath 503′ is therefore removably sealable tofill needle 414′. When not in use, fill needle sheath 503′ isaseptically sealed to fill needle 414′ and may be suspended fromsuspension stubs 1240 a and 1240 b as shown in FIG. 13. As will bedescribed later, an operator may install flow path 404 in chamber 420.In that process, fill needle sheath 503′ with fill needle 414′aseptically sealed to it, is positioned on suspension stubs 1240 a and1240 b.

Sheath removal station 413′ also comprises sheath engagement fingers1230 a and 1230 b for engaging with locating eyelets 1050 a and 1050 bof swab holder 1003. When swab holder 1003, either with or without swabholder cap 1002 engaged with it, is forced onto sheath engagementfingers 1230 a and 1230 b, the angled mutual orientation of sheathengagement fingers 1230 a and 1230 b forces apart clamping members 1030a and 1030 b of swab holder 1003. This action disengages swab holder cap1002 from swab holder 1003. Swab holder 1003 is therefore removablysealable to swab holder cap 1002. When not in use, swab holder 1003aseptically sealed to swab holder cap 1002 may be suspended fromsuspension stubs 1250 a and 1250 b as shown in FIG. 13. As will bedescribed later, at the start of the process of filling pharmaceuticalcontainers with pharmaceuticals in chamber 420, an operator may installswab holder 1003 aseptically sealed to swab holder cap 1002 onsuspension stubs 1250 a and 1250 b as per FIG. 13.

FIG. 14a shows robotic arm endpiece 1100 holding aseptically sealed fillneedle package 900 by engagement clips 510 a′ and 510 b′ of fill needlehub 502′. FIG. 14b shows robotic arm endpiece 1100 holding asepticallysealed swab package 1000 by engagement clips 1010 a and 1010 b of swabcap 1002.

In operation, fluid path 404 is sealed aseptically to controlledenvironment enclosure 420 and fill needle package 900 is suspended onsuspension stubs 1240 a and 1240 b of sheath removal station 413′ asshown in FIG. 13. Swab package 1000 is introduced into enclosure 420 andsuspended on stubs 1250 a and 1250 b of sheath removal station 413′ asshown in FIG. 13. Controlled environment enclosure 420 may now bedecontaminated using any of the various means previously described.Fluid path may now be unprotected by unsealing fill needle 414′ fillneedle sheath 503′. This may be done using robotic arm 415 as explainedabove at the hand of FIG. 12. This step leaves fill needle sheath 503′located on sheath engagement fingers 1220 a and 1220 b and fill needle414′ located on robotic arm endpiece 1100.

Swab holder cap 1002 may be similarly removed from swab holder 1003 toexpose swab 1006 to the environment in enclosure 420. The process leavesswab holder 1003 with swab 2006 located on sheath engagement fingers1230 a and 1230 b of sheath removal station 413′. Robotic arm 415 nowmay proceed to fill pharmaceutical vials 411 located on pedestal 412 inFIG. 1 with fluid via fill needle 414′. Fill needle 414′ and swab holdercap 1002 remain resident on robotic arm endpiece 1100 during the fillingprocess.

When filling has been completed, robotic arm 415 automatically movesrobotic arm endpiece 1100 with fill needle 414′ and swab holder cap 1002to sheath removal station 413′ to touch the dispensing end 506′ of fillneedle 414′ to the exposed tip 1008 of swab 1006.

Using robotic arm 415, eyelets 950 a and 950 b of fill needle sheath503′ are engaged with sheath engagement fingers 1220 a and 1220 b toallow fill needle 414′ to be aseptically sealed to fill needle sheath503′, thereby protecting the fluid path 404. Eyelets 1050 a and 1050 bof swab holder 1003 may similarly engage with sheath engagement fingers1230 a and 1230 b of sheath removal station 413′ to allow swab holder1003 and swab holder cap 1002 to be sealed aseptically to each other,thereby protecting the swab 2006. Fluid path 404 and sealed swab package1000 may now be removed from controlled environment enclosure 420.

As shown in FIG. 14 b, robotic arm endpiece 1100 has no moving parts andis capable of simultaneously bearing both fill needle package 900 andswab package 1000. Despite both robotic arm endpiece 1100 and sheathremoval station 413′ having no moving parts, they are jointly capable ofopening and closing both fill needle package 900 and swab package 1000.This is possible by virtue of the interaction between the engagementfingers 1220 a, 1220 b, 1230 a, 1230 b of sheath removal station 413′and the eyelets 950 a and 950 b of fill needle sheath 503′ and eyelets1050 a and 1050 b of swab holder 1003, combined with the spring-loadedor flexible nature of portions of fill needle sheath 503′ and swabholder 1003.

In one aspect of the invention, described at the hand of FIG. 15, amethod is provided for transferring (1500) within a controlledenvironment enclosure a fluid along a fluid path to a destination withinthe controlled environment enclosure, the method comprising providing(1510) an aseptically sealed fluid path comprising an aseptically sealedfill needle package, aseptically sealing (1520) the fluid path to thecontrolled environment enclosure, decontaminating (1530) the controlledenvironment enclosure after aseptically sealing the fluid path to thecontrolled environment enclosure, automatically unprotecting (1540) thefluid path within the controlled environment enclosure, transferring(1550) the fluid to the destination along the fluid path after theautomatically unprotecting, and disposing without re-using (1570) of thefluid path after transferring the fluid to the destination.

The automatically unprotecting (1540) may be by automatically operatinga robotic arm. The decontaminating (1530) the controlled environmentenclosure may automatically be done after the sealing the fluid path tothe controlled environment enclosure. The providing an asepticallysealed fluid path (1510) may comprise providing a fill needle removablyand aseptically sealed to a fill needle sheath and the sheath may be amonolithic injection molded polymeric fill needle sheath. The providingan aseptically sealed fluid path (1510) may comprise providing apre-sterilized tube aseptically sealed to the fill needle. Thetransferring (1550) the fluid to a destination may comprise transferringthe fluid to at least one of a culture of cells, a culture of tissue, anenzyme solution, a suspension of immobilized enzymes, a mix of activeingredients, and an excipient. The transferring (1550) the fluid may betransferring an aseptic fluid. The transferring (1550) within acontrolled environment enclosure may be transferring within an isolator.The transferring the fluid (1550) to a destination may comprise at leastone of transferring the fluid to microwell plates and to containers forpharmaceutical products.

The method may further comprise automatically protecting (1560) thefluid path after transferring the fluid to the destination and beforedisposing of the fluid path. The transferring (1550) the fluid maycomprise filtering the fluid in the fluid path. The filtering may besterile filtering.

As part of the method described above, a method (1500 a) is provided forinstalling a fluid path within a controlled environment enclosurecomprising, providing (1510) an aseptically sealed fluid path comprisingan aseptically sealed fill needle package, aseptically sealing (1520)the fluid path to the controlled environment enclosure, decontaminating(1530) the controlled environment enclosure after aseptically sealingthe fluid path to the controlled environment enclosure, andautomatically unprotecting (1540) the fluid path within the controlledenvironment enclosure. The automatically unprotecting may be byautomatically operating a robotic arm. The decontaminating thecontrolled environment enclosure may be automatically done after thesealing the fluid path to the controlled environment enclosure. Theproviding a fill needle may comprise providing a fill needle removablyand aseptically sealed to a fill needle sheath. The providing a fillneedle may comprise providing a fill needle removably and asepticallysealed to a monolithic injection molded polymeric fill needle sheath.

In a further aspect of the invention described at the hand of FIG. 16, amethod is provided for uninstalling (1600) from a controlled environmentenclosure a fluid path comprising a fill needle, the method comprisingautomatically aseptically sealing (1610) the fill needle to a monolithicinjection moulded polymeric fill needle sheath within the controlledenvironment enclosure, decontaminating (1640) the controlled environmentenclosure after aseptically sealing (1610) the fluid path, opening(1650) the controlled environment enclosure after the decontaminating(1640), and removing (1660) the fluid path from the controlledenvironment enclosure. The method may further comprise automaticallyswabbing (1620) a dispensing end of the fill needle with a swab andautomatically aseptically sealing the swab (1630) in a swab packagebefore decontaminating (1640) the controlled environment, and removing(1670) the swab package from the controlled environment enclosure afteropening the controlled environment enclosure.

The automatically aseptically sealing the fluid path (1610) may be byautomatically operating a robotic arm. The decontaminating (1640) thecontrolled environment enclosure may be done automatically after thesealing (1610) the fluid path. The opening (1650) the controlledenvironment enclosure is done automatically after the decontaminating(1640) the controlled environment enclosure. The automatically swabbing(1620) may be by automatically operating a robotic arm. Theautomatically aseptically sealing (1610) the fluid path may be byautomatically operating the robotic arm. The decontaminating (1640) thecontrolled environment enclosure may be done automatically after thesealing the fluid path (1610) and sealing the swab (1630). The swabbing(1620) may be with a swab disposed in a monolithic injection moldedpolymeric swab holder.

As part of the above methods, a subsidiary method is provided fordecontaminating a controlled environment enclosure containing a fluidpath having a fill needle, the method comprising automaticallyaseptically sealing (1610) the fill needle to a monolithic injectionmolded polymeric fill needle sheath within the controlled environmentenclosure, and decontaminating (1620) the controlled environmentenclosure after aseptically sealing (1610) the fluid path. Theautomatically aseptically sealing (1610) the fluid path may be byautomatically operating a robotic arm. A subsidiary method is alsoprovided for decontaminating a controlled environment enclosurecontaining a swab disposed in a swab holder, the method comprisingautomatically aseptically sealing the swab holder to a swab holder cap(1630) within the controlled environment enclosure, and decontaminating(1640) the controlled environment enclosure after aseptically sealingthe swab holder to a swab holder cap. The automatically asepticallysealing (1630) the swab holder to a swab holder cap may be byautomatically operating a robotic arm.

In the above-described embodiments, a pair of injection-molded parts aresnapped together using integrally molded leaf spring members withclamping clips that engage with locating ledges. This action provides apositive mechanical detent that ensures that the implement is reliablysealed inside the sheath. But one of ordinary skill in the art wouldrecognize that a variety of other types of mechanisms can be used toprovide this type of action, including but not limited to cam-basedmechanisms, ratcheting mechanisms, bistable linkages, spring-loadedballs, snaps, and latch pins.

The mechanisms in the above-described embodiments are presented inconfigurations that allow a concave sheath and cover-like hub to beengaged with each other along a vertical axis, but other geometricconfigurations can also be implemented. A pair of concave sheathportions could both partly enclose an implement in a downward-facingclamshell-type configuration, for example. And while the sheath and itscorresponding hub are preferably manufactured as two completely separateparts as described above, they could also be built as a compound unit,such as by connecting them with a hinge or tether.

The above-described embodiments also provide bearing surfaces onengagement clips and in eyelets that respectively interact with anendpiece on a robot arm and protrusions on a holding station, whichallow a robot arm to automatically open and close the sheath. But one ofordinary skill in the art would recognize that many other combinationsand arrangements of bearing surfaces could also be employed.

ADDITIONAL NOTES

The above detailed description includes references to the accompanyingdrawings, which form a part of the detailed description. The drawingsshow, by way of illustration, specific embodiments in which theinvention can be practiced. These embodiments are also referred toherein as “examples.” All publications, patents, and patent documentsreferred to in this document are incorporated by reference herein intheir entirety, as though individually incorporated by reference. In theevent of inconsistent usages between this document and those documentsso incorporated by reference, the usage in the incorporated reference(s)should be considered supplementary to that of this document; forirreconcilable inconsistencies, the usage in this document controls.

In this document, the terms “a” or “an” are used, as is common in patentdocuments, to include one or more than one, independent of any otherinstances or usages of “at least one” or “one or more.” In thisdocument, the term “or” is used to refer to a nonexclusive or, such that“A or B” includes “A but not B,” “B but not A,” and “A and B,” unlessotherwise indicated. In the appended claims, the terms “including” and“in which” are used as the plain-English equivalents of the respectiveterms “comprising” and “wherein.” Also, in the following claims, theterms “including” and “comprising” are open-ended, that is, a system,device, article, or process that includes elements in addition to thoselisted after such a term in a claim are still deemed to fall within thescope of that claim. Moreover, in the following claims, the terms“first,” “second,” and “third,” etc. are used merely as labels, and arenot intended to impose numerical requirements on their objects.

Method examples described herein can be machine or computer-implementedat least in part. Some examples can include a tangible computer-readablemedium or machine-readable medium encoded with instructions operable toconfigure an electronic device to perform methods as described in theabove examples. An implementation of such methods can include code, suchas microcode, assembly language code, a higher-level language code, orthe like. Such code can include computer readable instructions forperforming various methods. The code can form portions of computerprogram products. Further, the code can be tangibly stored on one ormore volatile or non-volatile computer-readable media during executionor at other times. These computer-readable media can include, but arenot limited to, hard disks, removable magnetic disks, removable opticaldisks (e.g., compact disks and digital video disks), magnetic cassettes,memory cards or sticks, random access memories (RAM's), read onlymemories (ROM's), and the like.

The above description is intended to be illustrative, and notrestrictive. For example, the above-described examples (or one or moreaspects thereof) may be used in combination with each other. Otherembodiments can be used, such as by one of ordinary skill in the artupon reviewing the above description. The Abstract is provided to complywith 37 C.F.R. § 1.72(b), to allow the reader to quickly ascertain thenature of the technical disclosure. It is submitted with theunderstanding that it will not be used to interpret or limit the scopeor meaning of the claims. Also, in the above Detailed Description,various features may be grouped together to streamline the disclosure.This should not be interpreted as intending that an unclaimed disclosedfeature is essential to any claim. Rather, inventive subject matter maylie in less than all features of a particular disclosed embodiment.Thus, the following claims are hereby incorporated into the DetailedDescription, with each claim standing on its own as a separateembodiment. The scope of the invention should be determined withreference to the appended claims, along with the full scope ofequivalents to which such claims are entitled.

What is claimed is:
 1. A pharmaceutical fill needle system fordispensing pharmaceutical fluids within an aseptic chamber, the fillneedle system comprising: a first sterilizable encapsulation portioncomprising at least one first mechanical engagement feature and a firstsealable surface; a fill needle aseptically sealed to the firstencapsulation portion and having a fluid receiving end and a fluiddispensing end, the fluid dispensing end protruding from the firstencapsulation portion; a sterilizable fluid path aseptically sealed tothe first encapsulation portion, a proximal end of the fluid path beingin fluid communication with the fluid receiving end of the fill needle;and a second sterilizable encapsulation portion comprising at least onesecond mechanical engagement feature and a second sealable surface, theat least one second mechanical engagement feature releasably engagedwith the at least one first mechanical engagement feature and the secondsealable surface aseptically sealed with the first sealable surface, thefirst and second encapsulation portions jointly asepticallyencapsulating the fill needle.
 2. The system of claim 1, furtherincluding a removal station having at least one engagement fingerwherein the first and second mechanical engagement features areconfigured for mutual disengagement and re-engagement by interactionwith the removal station in the aseptic chamber to uncover and cover thefill needle.
 3. The system of claim 1, wherein the fill needle assemblyis aseptically sealed before use.
 4. The system of claim 1, wherein thefill needle assembly is configured for being placed in fluidcommunication with a fluid source.
 5. The system of claim 4, furthercomprising a fluid path coupled to the fill needle assembly, an exteriorof the fluid path being configured to extend into the aseptic chamberthrough a sealed opening of the aseptic chamber.
 6. The system of claim5 further comprising a fluid container disposed outside of the asepticchamber, the fluid container being coupled to the fluid path.
 7. Thesystem of claim 6 wherein the fluid container further comprises an airfilter.
 8. The system of claim 1, wherein the fill needle assembly isconfigured for aseptic cleaning so that the fill needle assembly may bere-usable.
 9. The system of claim 1, wherein the first mechanicalengagement feature and the second mechanical engagement feature aremonolithic such that the mutual mating is achieved by the elasticity ofthe first and second mechanical engagement features.
 10. The system ofclaim 1, further comprising a tamper-evident feature disposed about atleast one of the first and second mechanical engagement features suchthat the tamper-evident feature indicates a breach of the encapsulationof the fill needle.
 11. The system of claim 1, wherein the encapsulationportion is aseptically sealed before use.
 12. The system of claim 1,wherein the encapsulation portion is configured for being placed influid communication with a fluid source.
 13. The system of claim 12,further comprising a fluid path coupled to the encapsulation portion, anexterior of the fluid path being configured to extend into the asepticenvironment through a sealed opening of an enclosure of the asepticenvironment.
 14. The system of claim 13 further comprising a fluidcontainer disposed outside of the aseptic environment, the fluidcontainer being coupled to the fluid path.
 15. The system of claim 14wherein the fluid container further comprises an air filter.
 16. Thesystem of claim 1, wherein the encapsulation portion is configured foraseptic cleaning so that the encapsulation portion may be re-usable. 17.The system of claim 1, wherein the first mechanical engagement featureand the second mechanical engagement feature are monolithic such thatthe mutual mating is achieved by the elasticity of the first and secondmechanical engagement features.
 18. The system of claim 1, furthercomprising a tamper-evident feature disposed about at least one of thefirst and second mechanical engagement features such that thetamper-evident feature indicates a breach of the sealed cavity.
 19. Thesystem of claim 1, wherein the encapsulation portion is substantiallycylindrical in shape.
 20. The system of claim 1, wherein the firstmechanical engagement feature portion has a locating ledge, the secondmechanical engagement feature has a clamping clip, and the locatingledge engages the clamping clip to mutually mate.
 21. The system ofclaim 1, wherein the encapsulation portion further includes at least twoengagement clips configured for engaging with a robotic arm end piece.22. The system of claim 2, wherein the second mechanical engagementfeature further includes at least two eyelet portions, the eyeletportions defining a void configured to receive the at least oneengagement finger of the removal station.
 23. The system of claim 22,wherein the second mechanical engagement feature comprises anelastomeric material.
 24. The system of claim 23, wherein theelastomeric material is a steam permeable elastomeric material.
 25. Thesystem of claim 1, wherein at least one of the first mechanicalengagement feature and the second mechanical engagement feature comprisean elastomeric material.
 26. The system of claim 25, wherein theelastomeric material is a steam permeable elastomeric material.
 27. Thesystem of claim 1, further comprising an o-ring disposed between thefirst sealable portion and the second sealable portion.